UA75070C2 - A method for synthesis of perindopril and its pharmaceutically acceptable salts - Google Patents

Abstract

The invention concerns a method for synthesis of perindopril of formula (I) and its pharmaceutically acceptable salts. (І)

Description

the amount of triethylamine, less than or equal to 0.25 of the compounds of the formulas (II) and (II), less than 0.295 and 0.190 mol per mol of the compound of the formula (II) used. respectively 6. The method of synthesis according to any of paragraphs 1-5, which differs from H in that the compound of the formula (MI) contains - impurities of the compounds of the formulas (MII) and (MI), less than 1.595

H 1 on : | "VSh ne i OVp y ko o "V m (1) ns Me SN

From whom about

M. M. (MI) Master of Science

S. M. O., N

Fa - yi on : EM nen

M | OVp with co

N (PO). poko (in) 0-27 sec,

M (Iii) sha

AT--. sleep I (Appendix 7. The method of synthesis according to any of paragraphs 1-6, which differs in that perindopril contains impurities

The present invention relates to a method for the enzyme that converts angiotensin I! (or kinetics of the industrial synthesis of perindopril of the formula (1): nazu Ii), which makes it possible, on the one hand, to prevent

Inhibition of conversion of angiotensin decapeptide na - octapeptide angiotensin I! (vasoconstrictor 2 agent) and, on the other hand, preventing the cleavage of bradykinin (a vasodilator) into an inactive peptide. These two actions contribute to positive

And sleep effect of perindopril in cardiovascular n 2 (I) diseases, especially arterial hypertension and HF, heart failure. n.e. Perindopril, its preparation and its therapeutic use were described in the European

MN "to patent description EP 0049658.

Considering the pharmaceutical interest in (5) this compound, it is important to be able to obtain it by an efficient industrial method of synthesis, which can be easily applied on an industrial scale and its pharmaceutically acceptable salts, giving perindopril in good yield.

Perindopril, as well as its pharmaceutical dom and, mainly, with an excellent degree of cis- acceptable salts, and especially its tert-butylamine tote. salt, have valuable pharmacological properties. Patent description EP 0308341 characterizes industrial synthesis of perindopril by binding - their main property is inhibition of (25,3a5,7a5)-octahydroindole-2-carboxylic acid benzyl ether C-((5)-1-) using this method is not satisfactory, and carboxybutyl|-(5)-alanine with ethyl ether, undergoes purification stages in order to obtain carboxyl-perindopril of such a quality that could allow the catalytic hydrogenation of the heterocycle group and its use as a pharmaceutical active ingredient. .

This method has the advantage of obtaining perindopril. by the amounts of impurities of formulas (II) and (1):

However, the purity of perindopril obtained by

N

: SYA, (Tov /

RK. x - neo o x CH, (U)

Mai A Zh

Ф) red vo z" МН ЗСО о in ethyl acetate, in the presence of an amount of from 0.4 to 0.0 bmol of 1-hydroxybenzotriazole per mol of the compound of the formula (IM) used and in the presence of an amount of from 1 to n 1.2 mol of dicyclohexylcarbodiimide per mole of

E of the compound of the formula (IM), in its absence

of triethylamine or in the presence of an amount of triethylamine less than or equal to Tmol per mol of the compound of the formula (IM) used, preferably less than or equal to 0.25 mol per mol of the compound of the formula (IM) used, at a temperature from 20 to 77"C, with

Also by obtaining, after isolation, compounds of the formula

Because sleep, ! schi (MI): o : (PO).

Currently, the applicant has developed a new industrial method of synthesis, which yields perindopril - СО,Ва with a degree of purity that is compatible with its use as a pharmaceutical active ingredient, o; CH, (U with levels of impurities of formulas (II) and (III), less Ko than 0.295 and 0.195, respectively. (5)

More specifically, the present invention relates to a method for the industrial synthesis of perindopril, which is characterized by the fact that the benzyl 5) ether of the formula (IM): CO, n where Vp represents a benzyl group, : o CH the carboxyl group of the heterocycle from which 3 is deprived protection by catalytic hydrogenation with ode-

Fo o SU with perindopril formula (I),

In M SO Va ZE which is converted, if desired, into far-

In 7 of them, a macologically acceptable salt, such as tert-o-butylamine salt. . This method is of particular interest for (M) for the following reasons: where Vp represents a benzyl group, reacts with Coupling in an alkaline medium with a benzylic compound of the formula (M): th ether of the formula (IM) with a compound of the formula (M) has been described in the patent description EP 0308341, but under the specified conditions (use of moles of the compound of the formula (M), moles of triethylamine, 3.8 moles of 1-hydroxybenzotriazole and 2.9 moles of dicyclohexylcarbodiimide per mole of the used compound of the formula (IM)) numerous secondary products are formed - you

In particular, the obtained compound of the formula (MI) mis-

contains significant amounts (from 595 to 1595) of lsulfonate impurities, 0.0 bkg of triethylamine, 4.bl of ethylaceformulas (MIII) and (MIII), which, during debenzation and then, after stirring for 10 minutes, turn into impurities of formulas (II) and minutes at ambient temperature (11) higher, 0.52 kg of M-((5)-ethoxycarbonyl-1-butyl|-(5)- n H alanine, 0.15 kg of 1-hydroxybenzotriazole and 0 ,5 kg

H, E of dicyclohexylcarbodiimide. Next, this heterogeneous mixture is brought to 30"C for 3 hours with vigorous stirring, after which it is cooled

The filtrate is further washed and then evaporated to a dry residue, obtaining the expected product with a yield of 9295. 1-C25)-2-((15)-1-

M M (Ethoxycarbonyl)-butylamino|-propionyl)-octahydro-o o 1H-indole-2-carboxylic acid

The residue obtained at the previous stage (1 kg) is dissolved in Tl of methylcyclohexane, and the solution is transferred to the hydrogenator; then 1 kg of palladium-on-coal 5906 palladium-on-coal suspended in the unexpectedly discovered that the reduction of 0.4 l of methylcyclohexane, followed by the addition of 3.2 l of the amount or even the absence of triethylamine in the water of the binding stage made it possible to limit the mixture. for- No oh!

M ly (M) to ok formulas b (MT) In uci for at a temperature from 15 to 30"C until it is

In and and in, absorbed theoretical amount of hydrogen. - Catalytic hydrogenation of the compound of the formula After removal of the catalyst by filtration (MU), thus yielding perindopril, the aqueous phase of the filtrate is washed with much better purity, and, in particular, with the levels of impurities with tylcyclohexane and then lyophilized, obtaining the formula (I ) and (II), less than 0.295 and 0.190, respectively: - I know the expected product with a yield of 94905. re shodo Example 3: (25,3a5,7a5)-1-(25)-2-((15 )-1- in addition, reduction; on, pi binding, (ethoxycarbonyl)-butylamino|-propionyl-octahydro-. In the form of '. 1H-indole-2-carboxylic acid tert-butylamine hydroxybenzotriazole and dicyclohexylcarbodisil (Moz Lyophilizate obtained at the previous stage of dressing, oristine grains (Ikg) are dissolved in 14 liters of ethyl acetate in alcohol with the same formula, then added zyvic from six persons. 2 kg of tert-butylamine and 2 liters of ethyl acetate.

Ge o nts, such as the written defects ab nasa- The obtained suspension is further heated with the svorogat pyzhchenavelny. we spa; Allow the mixture to cool in a refrigerator until complete development is achieved.

Example 1: Benzyl (25325 7ta8)-1-(25)-2- is filtered hot, and cooled, with stirring, to a temperature of 15-20 C. icar U r Then the precipitate obtained is filtered off, again octahydro-1H-indole-2-carboxylate

Place in the reaction apparatus, turn it into a paste with the help of ethylacetation of TKg (25325 7az)-octahydroindole-?

What is the forged product with a yield of 9590. carboxylic acid of benzyl ether of paratoluene

Computer layout L. Kupenko Signature Circulation 26 approx.

Ministry of Education and Science of Ukraine

State Department of Intellectual Property, str. Urytskogo, 45, Kyiv, MSP, 03680, Ukraine

SE "Ukrainian Institute of Industrial Property", str. Glazunova, 1, Kyiv - 42, 01601